rs140214637

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The ENST00000359321.2(XRCC2):ā€‹c.283A>Gā€‹(p.Ile95Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,613,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I95L) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.00015 ( 0 hom., cov: 32)
Exomes š‘“: 0.00042 ( 0 hom. )

Consequence

XRCC2
ENST00000359321.2 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.0470
Variant links:
Genes affected
XRCC2 (HGNC:12829): (X-ray repair cross complementing 2) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene is involved in the repair of DNA double-strand breaks by homologous recombination and it functionally complements Chinese hamster irs1, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0667395).
BP6
Variant 7-152649202-T-C is Benign according to our data. Variant chr7-152649202-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127954.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000422 (617/1461522) while in subpopulation NFE AF= 0.000541 (602/1112000). AF 95% confidence interval is 0.000505. There are 0 homozygotes in gnomad4_exome. There are 314 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
XRCC2NM_005431.2 linkuse as main transcriptc.283A>G p.Ile95Val missense_variant 3/3 ENST00000359321.2 NP_005422.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
XRCC2ENST00000359321.2 linkuse as main transcriptc.283A>G p.Ile95Val missense_variant 3/31 NM_005431.2 ENSP00000352271 P1
XRCC2ENST00000495707.1 linkuse as main transcriptn.305A>G non_coding_transcript_exon_variant 3/31
XRCC2ENST00000698506.1 linkuse as main transcriptc.115A>G p.Ile39Val missense_variant 2/2 ENSP00000513758

Frequencies

GnomAD3 genomes
AF:
0.000151
AC:
23
AN:
152214
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000309
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000243
AC:
61
AN:
250976
Hom.:
0
AF XY:
0.000251
AC XY:
34
AN XY:
135674
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000519
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000422
AC:
617
AN:
1461522
Hom.:
0
Cov.:
32
AF XY:
0.000432
AC XY:
314
AN XY:
727058
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000541
Gnomad4 OTH exome
AF:
0.000232
GnomAD4 genome
AF:
0.000151
AC:
23
AN:
152214
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000309
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000411
Hom.:
0
Bravo
AF:
0.000193
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000329
AC:
40
EpiCase
AF:
0.000218
EpiControl
AF:
0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, no assertion criteria providedcurationLeiden Open Variation DatabaseMay 02, 2012Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 95 of the XRCC2 protein (p.Ile95Val). This variant is present in population databases (rs140214637, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 22464251, 23054243, 26689913, 28767289). ClinVar contains an entry for this variant (Variation ID: 127954). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XRCC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect XRCC2 function (PMID: 27233470). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 02, 2018This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submittercurationSema4, Sema4Dec 17, 2020- -
Fanconi anemia complementation group U Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxOct 09, 2017This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
XRCC2-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 08, 2021This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
0.019
DANN
Benign
0.26
DEOGEN2
Benign
0.12
T
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.081
N
LIST_S2
Benign
0.58
T
M_CAP
Benign
0.0054
T
MetaRNN
Benign
0.067
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.73
N
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.52
N
REVEL
Benign
0.12
Sift
Benign
0.36
T
Sift4G
Benign
0.37
T
Polyphen
0.013
B
Vest4
0.084
MVP
0.072
MPC
0.035
ClinPred
0.046
T
GERP RS
-5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.015
gMVP
0.22

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140214637; hg19: chr7-152346287; API